scholarly journals Unleashing the Diagnostic, Prognostic and Therapeutic Potential of the Neuronostatin/GPR107 System in Prostate Cancer

2020 ◽  
Vol 9 (6) ◽  
pp. 1703
Author(s):  
Prudencio Sáez-Martínez ◽  
Juan M. Jiménez-Vacas ◽  
Antonio J. León-González ◽  
Vicente Herrero-Aguayo ◽  
Antonio J. Montero Hidalgo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Potential ◽  
Molecular Response ◽  
Oncogenic Signaling ◽  
Antitumor Effects ◽  
Normal Prostate ◽  
Migration Rates ◽  
Splicing Variants ◽  
Pathophysiological Role ◽  
Oncogenic Signaling Pathways

Certain components of the somatostatin-system play relevant roles in Prostate Cancer (PCa), whose most aggressive phenotype (Castration-Resistant-PCa (CRPC)) remains lethal nowadays. However, neuronostatin and the G protein-coupled receptor 107 (GPR107), two novel members of the somatostatin-system, have not been explored yet in PCa. Consequently, we investigated the pathophysiological role of NST/GPR107-system in PCa. GPR107 expression was analyzed in well-characterized PCa patient′s cohorts, and functional/mechanistic assays were performed in response to GPR107-silencing and NST-treatment in PCa cells (androgen-dependent (AD: LNCaP) and androgen-independent (AI: 22Rv1/PC-3), which are cell models of hormone-sensitive and CRPC, respectively), and normal prostate cells (RWPE-1 cell-line). GPR107 was overexpressed in PCa and associated with key clinical parameters (e.g., advance stage of PCa, presence of vascular invasion and metastasis). Furthermore, GPR107-silencing inhibited proliferation/migration rates in AI-PCa-cells and altered key genes and oncogenic signaling-pathways involved in PCa aggressiveness (i.e., KI67/CDKN2D/MMP9/PRPF40A, SST5TMD4/AR-v7/In1-ghrelin/EZH2 splicing-variants and AKT-signaling). Interestingly, NST treatment inhibited proliferation/migration only in AI-PCa cells and evoked an identical molecular response than GPR107-silencing. Finally, NST decreased GPR107 expression exclusively in AI-PCa-cells, suggesting that part of the specific antitumor effects of NST could be mediated through a GPR107-downregulation. Altogether, NST/GPR107-system could represent a valuable diagnostic and prognostic tool and a promising novel therapeutic target for PCa and CRPC.

scholarly journals MZF1 and SCAND1 Reciprocally Regulate CDC37 Gene Expression in Prostate Cancer

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 792 ◽  
Author(s):  
Takanori Eguchi ◽  
Thomas L. Prince ◽  
Manh Tien Tran ◽  
Chiharu Sogawa ◽  
Benjamin J. Lang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Heat Shock Protein 90 ◽  
Prostate Cancer Cells ◽  
Oncogenic Signaling ◽  
Normal Prostate ◽  
Elevated Expression ◽  
The Stability ◽  
Oncogenic Signaling Pathways

Cell division control 37 (CDC37) increases the stability of heat shock protein 90 (HSP90) client proteins and is thus essential for numerous intracellular oncogenic signaling pathways, playing a key role in prostate oncogenesis. Notably, elevated expression of CDC37 was found in prostate cancer cells, although the regulatory mechanisms through which CDC37 expression becomes increased are unknown. Here we show both positive and negative regulation of CDC37 gene transcription by two members of the SREZBP-CTfin51-AW1-Number 18 cDNA (SCAN) transcription factor family—MZF1 and SCAND1, respectively. Consensus DNA-binding motifs for myeloid zinc finger 1 (MZF1/ZSCAN6) were abundant in the CDC37 promoter region. MZF1 became bound to these regulatory sites and trans-activated the CDC37 gene whereas MZF1 depletion decreased CDC37 transcription and reduced the tumorigenesis of prostate cancer cells. On the other hand, SCAND1, a zinc fingerless SCAN box protein that potentially inhibits MZF1, accumulated at MZF1-binding sites in the CDC37 gene, negatively regulated the CDC37 gene and inhibited tumorigenesis. SCAND1 was abundantly expressed in normal prostate cells but was reduced in prostate cancer cells, suggesting a potential tumor suppressor role of SCAND1 in prostate cancer. These findings indicate that CDC37, a crucial protein in prostate cancer progression, is regulated reciprocally by MZF1 and SCAND1.

scholarly journals SCAND1 Suppresses CDC37 Gene Transcription by Repressing MZF1

2019 ◽  
Author(s):  
Takanori Eguchi ◽  
Thomas L. Prince ◽  
Tien Manh Tran ◽  
Chiharu Sogawa ◽  
Benjamin J. Lang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Gene Transcription ◽  
Cancer Progression ◽  
Prostate Cancer Cells ◽  
Oncogenic Signaling ◽  
Normal Prostate ◽  
Elevated Expression ◽  
The Stability ◽  
Oncogenic Signaling Pathways

Cell division control 37 (CDC37) increases the stability of HSP90 client proteins and is thus essential for numerous intracellular oncogenic signaling pathways, playing a key role in prostate oncogenesis. Notably, elevated expression of CDC37 was found in prostate cancer cells, although the regulatory mechanisms through which CDC37 expression becomes increased are unknown. Here we show both positive and negative regulation of CDC37 gene transcription by two members of the SCAN transcription factor family- MZF1 and SCAND1, respectively. Consensus DNA-binding motifs for myeloid zinc finger 1 (MZF1 / ZSCAN6) were abundant in the CDC37 promoter region. MZF1 became bound to these regulatory sites and trans-activated the CDC37 gene whereas MZF1 depletion decreased CDC37 transcription and reduced tumorigenesis of prostate cancer cells. On the other hand, SCAND1, a zinc-fingerless SCAN box protein that potentially inhibits MZF1, accumulated at MZF1-binding sites in CDC37 gene, negatively regulated CDC37 gene and inhibited tumorigenesis. SCAND1 was abundantly expressed in normal prostate cells but was reduced in prostate cancer cells, suggesting a potential tumor suppressor role of SCAND1 in prostate cancer. These findings indicate that CDC37, a crucial protein in prostate cancer progression, is regulated reciprocally by MZF1 and SCAND1.

scholarly journals SCAND1 suppresses CDC37 gene transcription by repressing MZF1

2019 ◽  
Author(s):  
Takanori Eguchi ◽  
Thomas L. Prince ◽  
Manh Tien Tran ◽  
Chiharu Sogawa ◽  
Benjamin J. Lang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Gene Transcription ◽  
Cancer Progression ◽  
Prostate Cancer Cells ◽  
Oncogenic Signaling ◽  
Normal Prostate ◽  
Elevated Expression ◽  
The Stability ◽  
Oncogenic Signaling Pathways

AbstractCDC37 increases the stability of HSP90 client proteins and is essential for numerous intracellular oncogenic signaling pathways. Elevated expression of CDC37 was found in prostate cancer cells, although the regulatory mechanisms through which CDC37 expression becomes increased are unknown. Here we show both positive and negative regulation of CDC37 gene transcription by two members of the SCAN transcription factor family- MZF1 and SCAND1, respectively. Consensus DNA-binding motifs for MZF1 were abundant in the CDC37 promoter region. MZF1 became bound to these regulatory sites and trans-activated the CDC37 gene whereas MZF1 depletion decreased CDC37 transcrption and reduced tumorigenesis of prostate cancer cells. On the other hand, SCAND1, a zinc-fingerless SCAN box protein that potentially inhibits MZF1, accumulated at MZF1-binding sites in CDC37 gene, negatively regulated CDC37 gene and inhibited tumorigenesis. SCAND1 was abundantly expressed in normal prostate cells but was reduced in prostate cancer cells, suggesting a potential tumor suppressor role of SCAND1 in prostate cancer. These findings indicate that CDC37, a crucial protein in prostate cancer progression, is regulated reciprocally by MZF1 and SCAND1.

scholarly journals The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1887 ◽  
Author(s):  
Francesco Bonollo ◽  
George N. Thalmann ◽  
Marianna Kruithof-de Julio ◽  
Sofia Karkampouna
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Therapy Resistance ◽  
Cancer Associated Fibroblasts ◽  
Metastatic Progression ◽  
Normal Prostate ◽  
Prostate Tumorigenesis

Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

scholarly journals Therapeutic Potential of Gnetin C in Prostate Cancer: A Pre-Clinical Study

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3631
Author(s):  
Ketaki Gadkari ◽  
Urvi Kolhatkar ◽  
Rutu Hemani ◽  
Gisella Campanelli ◽  
Qing Cai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Therapeutic Potential ◽  
Inhibitory Effects ◽  
Antitumor Effects ◽  
Anticancer Effects ◽  
Potent Inhibition ◽  
Avian Erythroblastosis Virus

Natural stilbenes have gained significant attention in the scientific community owing to their potential anticancer effects against prostate cancer. We recently reported that Gnetin C, a resveratrol (Res) dimer, demonstrated more potent inhibition of metastasis-associated protein 1/v-ets avian erythroblastosis virus E26 oncogene homolog 2 (MTA1/ETS2) axis in prostate cancer cell lines than other stilbenes. In this study, we investigated in vivo antitumor effects of Gnetin C in two doses (50 and 25 mg/kg, i.p.) using PC3M-Luc subcutaneous xenografts and compared these to Res and pterostilbene (Pter). We found that while vehicle-treated mice revealed rapid tumor progression, compounds-treated mice showed noticeable delay in tumor growth. Gnetin C in 50 mg/kg dose demonstrated the most potent tumor inhibitory effects. Gnetin C in 25 mg/kg dose exhibited tumor inhibitory effects comparable with Pter in 50 mg/kg dose. Consistent with the effective antitumor effects, Gnetin C-treated tumors showed reduced mitotic activity and angiogenesis and a significant increase in apoptosis compared to all the other groups. The data suggest that Gnetin C is more potent in slowing tumor progression in prostate cancer xenografts than Res or Pter. Taken together, we demonstrated, for the first time, that Gnetin C is a lead compound among stilbenes for effectively blocking prostate cancer progression in vivo.

scholarly journals Unraveling the Therapeutic Potential of GANT61/Dactolisib Combination as a Novel Prostate Cancer Modality

2021 ◽  
Author(s):  
Mohamed youssef ◽  
Nermine Moussa ◽  
Maged W. Helmy ◽  
Medhat Haroun
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Protein Kinase ◽  
Cyclin D1 ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
Antitumor Effects ◽  
Protein Levels ◽  
Pc3 Cells ◽  
Active Caspase

Abstract Aberrant activation of several signaling pathways has been implicated in prostate cancer (PCa) progression to castrate-resistant prostate cancer (CRPC). Phosphoinositide-3-kinase/Protein Kinase B/mechanistic Target of Rapamycin (PI3K/AKT/mTOR) and Hedgehog/GLI (Hh/GLI) pathways are major participants in progression to CRPC. In this sense, the current work aims to assess the potential antitumor effects resulting from co-targeting the aforementioned pathways in PC3 cells with Dactolisib as a dual PI3K/mTOR inhibitor and GANT61 as a GLI1 antagonist. Three replica of PC3 cells were assigned for four treatment groups; vehicle control, Dactolisib-treated, GANT61-treated, and combination-treated groups. GLI1 gene expression was determined by quantitative real-time PCR while active caspase-3 was determined colorimetrically. P-AKT, p70 ribosomal s6 protein kinase 1 (pS6K1), cyclin D1, vascular endothelial growth factor 1 (VEGF1), and Microtubule-associated proteins 1A/1B light chain 3 (LC3) protein levels were determined by ELISA technique. GLI1 gene expression was down-regulated as a result of Dactolisib, GANT61, and their combination. Additionally, both drugs significantly reduced p-AKT, pS6K1, cyclin D1, and VEGF1 protein levels. Dactolisib elevated LC3 protein levels and GANT61 augmented Dactolisib effect on LC3. Moreover, only Dactolisib/GANT61combination significantly increased active caspase-3 level. To sum up, Dactolisib/GANT61 combination was shown to be promising in PCa treatment. Further in-vitro and in-vivo studies are warranted to support our findings.

scholarly journals Structure-Based Design of Novel Benzimidazole Derivatives as Pin1 Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1198 ◽  
Author(s):  
Shuxiang Wang ◽  
Lihong Guan ◽  
Jie Zang ◽  
Kun Xing ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antiproliferative Activity ◽  
Inhibitory Activity ◽  
Benzimidazole Derivatives ◽  
Human Prostate Cancer ◽  
Oncogenic Signaling ◽  
Oncogenic Pathways ◽  
Ic50 Values ◽  
Oncogenic Signaling Pathways

Peptidyl-prolyl cis/trans isomerase Pin1 plays a key role in amplifying and translating multiple oncogenic signaling pathways during oncogenesis. The blockade of Pin1 provided a unique way of disrupting multiple oncogenic pathways and inducing apoptosis. Aiming to develop potent Pin1 inhibitors, a series of benzimidazole derivatives were designed and synthesized. Among the derivatives, compounds 6h and 13g showed the most potent Pin1 inhibitory activity with IC50 values of 0.64 and 0.37 μM, respectively. In vitro antiproliferative assay demonstrated that compounds 6d, 6g, 6h, 6n, 6o and 7c exhibited moderate antiproliferative activity against human prostate cancer PC-3 cells. Taken together, these unique benzimidazole derivatives exhibited great potential to be further explored as potent Pin1 inhibitors with improved potency.

scholarly journals Dach1-Variant 4 Plays an Oncogenic Role and Promotes Radioresistance in Prostate Cancer

2021 ◽  
Author(s):  
Ilenia Giordani ◽  
Carlo M. Scornajenghi ◽  
Francesco Marampon ◽  
Antonella Stoppacciaro ◽  
Silvia Di Agostino ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Western Blot ◽  
Functional Role ◽  
Nuclear Staining ◽  
Western Blots ◽  
Normal Prostate ◽  
Mesenchymal Transition ◽  
Splicing Variants ◽  
Pc3 Cells

Abstract Background: Human Dachshund homologue 1 (DACH1) is involved in carcinogenesis with opposite roles reported in different tumor types. Four alternatively spliced transcripts encoding different DACH1 isoforms were described but their specific role in human cancers is still unknown. Prostate cancer (PCa) is a heterogeneous disease with a very wide variability, so there is yet a relevant need to find new diagnostic and therapeutic biomarkers to make a safe clinical evaluation. It is well known that the differential expression of protein isoforms can induce distinct transcriptional programs with opposing effects on tumor progression and therapy. Thus, in this study we aimed to correlate the functional role of DACH1 with its splicing variants expression in PCa.Methods: The expression and functional role of DACH1 splicing variants in PCa were investigated using tumor (PC3) and normal (RWPE-1) cell lines, patient biopsies and TCGA dataset. Flow-cytometry, western blots and RT-qPCR were used for in vitro molecular characterization; invasion, adhesion, clonogenic assays and cell cycle analysis for functional characterization. Immunohystochemistry and western blot were performed on human PCa biopsies.Results: RT-qPCR and Western Blot revealed that DACH1-positive PC3 cells predominantly expressed DACH1 variant 4 (DACH1-v4), whereas RWPE-1 cells mostly expressed DACH1 variant 3. Stable DACH1-v4 overexpression enhanced the transformed phenotype of PC3 cells by inducing proliferation, colony formation, invasion ability, epithelial to mesenchymal transition. Given its intrinsic radioresistance, PCa frequently recurs after radiotherapy. Of note, DACH1-v4-overexpressing PC3 cells displayed higher radioresistant behavior. Overexpression of DACH1-v4 also transformed RWPE-1 cells to oncogenic phenotype, suggesting a pro-oncogenic role for this specific isoform. PCa biopsies analysis showed DACH1 nuclear staining enhanced throughout the increase of the tumor grade. Remarkably, tumor glands were found to express a long DACH1 variant, while normal prostate tissue expressed the short DACH1 isoform, in line with data from TCGA-PRAD analysis and our data in RWPE-1 cells. Conclusions: Our findings highlight the oncogenic role of DACH1-v4 in PCa and suggest that the longer DACH1 variants could be associated to pro-tumor function, while the shortest DACH1 variant would perform tumor suppression. The expression of specific DACH1 isoforms could represent a novel diagnostic/prognostic marker in PCa.

scholarly journals HMGB1: A Promising Therapeutic Target for Prostate Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Munirathinam Gnanasekar ◽  
Ramaswamy Kalyanasundaram ◽  
Guoxing Zheng ◽  
Aoshuang Chen ◽  
Maarten C. Bosland ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
High Mobility ◽  
Chromatin Binding ◽  
Oncogenic Signaling ◽  
Prostate Cancer Treatment ◽  
Promising Therapeutic Target ◽  
Prostate Cancer Development ◽  
Oncogenic Signaling Pathways

High mobility group box 1 (HMGB1) was originally discovered as a chromatin-binding protein several decades ago. It is now increasingly evident that HMGB1 plays a major role in several disease conditions such as atherosclerosis, diabetes, arthritis, sepsis, and cancer. It is intriguing how deregulation of HMGB1 can result in a myriad of disease conditions. Interestingly, HMGB1 is involved in cell proliferation, angiogenesis, and metastasis during cancer progression. Furthermore, HMGB1 has been demonstrated to exert intracellular and extracellular functions, activating key oncogenic signaling pathways. This paper focuses on the role of HMGB1 in prostate cancer development and highlights the potential of HMGB1 to serve as a key target for prostate cancer treatment.

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